IMMUNE LIVER DISEASE Prof Dr Amr Aly Abd

IMMUNE LIVER DISEASE Prof. Dr. Amr Aly Abd El Moety Hepatobiliary Unit

3 - Autoimmune hepatitis (AIH) is a self-perpetuating hepatocellular inflammation of unknown cause. It is characterized by: • The presence of interface hepatitis on histologic examination. • Hypergammaglobulinemia, and autoantibodies in the serum. • Diagnosed after exclusion of other chronic liver diseases.

Interface hepatitis The limiting plate of the portal tract is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis

Diagnostic criteria 1. The propensity for an acute and rarely fulminant hepatitis. 2. Presence of lobular hepatitis. 3. Cholestatic histologic changes; • Including bile injury and dectopenia.

Diagnostic criteria Lobular hepatitis Mononuclear inflammatory cells line the sinusoidal spaces. Typically, lobular hepatitis coexists with interface hepatitis, but it may be pronounced during acute

Diagnostic criteria 4. Immunoserologic tests A. Antinuclear antibodies (ANA). B. Smooth muscle antibodies (SMA). C. Liver/kidney microsome type 1 (anti-LKM 1). D. Perinuclear anti-neutrophil cytoplasmic antibodies (p. ANCAs) are common in type 1 AIH.

Clinical criteria A. The definite diagnosis of AIH requires: The exclusion of other similar diseases. Laboratory findings that indicate substantial immunoreactivity. Histologic features of interface hepatitis.

Clinical criteria B. A probable diagnosis Is justified when findings are compatible with AIH but insufficient of a definite diagnosis. Patients who lack conventional autoantibodies but who are seropositive for investigational markers. Such as antibodies to the asialoglycoprotein receptor (anti. ASGPR), soluble liver antign/liver-pancreas (anti. SLA/LP), actin (antiactin), or liver cytosol type 1 (anti. LC 1), are classified as having a probable disease.

Diagnostic algorithm for autoimmune hepatitis Abnormal AST and GG levels AST: Alkaline Phosphatase > AMA- ceruloplasmin normal α 1 antitrypsin phenotype normal Normal or nonspecific iron level HBs. Ag, anti –HCV, Ig. M anti-HAV- Interface hepatitis ± lobular hepatitis Definite GG ≥ 1. 5 normal ANA, SMA or LKM 1 ≥ 1: 80 No drugs or blood products Alcohol < 25 gm/d Type 1 ANA and/or SMA+ Probable GG ≥ 1. 5 normal ANA, SMA or LKM 1 ≥ 1: 40 Previous drugs or blood products Alcohol use Other liver-related authoantibodies Type 2 LKM 1+

Pathogenesis The pathogenic mechanisms of AIH are unknown. The most popular hypotheses evoke a constellation of interactive factors that include; • A triggering agent (infectious agents, drugs, and toxins). • A genetic predisposition. • Autoantigen display, immunocyte activation, and effector cell expansion.

Pathogenesis The antigen binding groove of the class II molecule of the major histocompatibility complex (MHC) is encoded by alleles that determine its configuration and its ability to activate immunocytes. The susceptibility alleles of AIH reside on the DRB 1 gene, and among white northern European and north American patients, they are DRB 1*0301 and DRB 1*0401.

Pathogenesis Different ethnic groups have different susceptibility alleles, and these findings support a shared motif hypothesis of pathogenesis. According to this hypothesis, risk of disease relates to amino acid sequences in the antigen binding groove of the class II MHC molecule, and multiple alleles encode the same or a similar sequence (shared motif).

Pathogenesis The critical shared motif in AIH in white northern Europeans and North Americans is represented by the six-amino-acid code LLEQKR, where lysine (K) is in position 71 of the DRβ polypeptide chain of the class II MHC molecule. DRB 1*0301 and DRB 1*0401 encode identical sequences in this region. DRB 1*0404 and DRB 1*0405, which are the susceptibility alleles in Mexican, Japanese, and Argentine adults, encode a similar sequence except for an arginine (R) for lysine (K) at DRβ 71 position.

Pathogenesis The critical six-amino-acid motif in AIH restricts the range of peptides that can be accommodated. Only the cytochrome monooxygenase p-450 ii. D 6 (CYP 2 D 6) has been recognized as a target auto antigen in AIH.

Liver cell destruction is by Cell-mediated coytotoxicity, antibody-dependent cellmediated cytotoxicity, or a combination of both mechanisms Subclassifications Three types of AIH have been proposed on the basis of immunoserologic markers.

Sub classifications of autoimmune Hepatitis based on Auto antibodies Liver/kidney microsome type 1 None p. ANCA actin Asialoglycoprotein receptor possible CYP 2 D 6 Transfer ribonucleoprotein (t. RNP) involved in selenocysteine metabolism Age (years) Bimodal (10 -20 and 4570) Pediatric(2 -14) Adults (30 -50) Women (%) 78 89 90 Concurrent immune diseases (%) 41 34 58 Organ-specific antibodies (%) 4 30 Uncertain Marked No Mild Occasional Moderate No HLA associations -B 8 -DR 3, -c 4 A -B 14, -DR 3, -C 4 A-Q 0, -DR 7 Uncertain Allelic risk factors DRB 1*0301 and *0401 (white North Americans northern Europeans DRB 1*07 (Germans and Brazilians) Uncertain +++ +++ Conventional autoantibodies Novel autoantiboies Gamma globulin Elevation Low lg. A Glucocorticoid responsive Smooth muscle nuclear

Variant form of autoimmune hepatitis Clinical AIH features ANA and/or AIH features AMA present CUC SMA present No auto antibodies AMA absent HLA-B 8 or-DR 3 Abnormal cholangiogram NO CUC Normal cholangiogram Histologic Cholangitis Interface hepatitis Cholangitis Treatment Empirical prednisone Empirical prtdnisone Empirical if AP≤ twice normal; and ursodeoxycholic Empirical prednisone and acid if AP> twice conventional ursodeoxycholic acid if And/OR normal and/or florid regimens for AIH AP> twice normal and/or ursodeoxycholic acid duct lesions florid duct lesions

Prevalence Among white northern Europeans is 1. 9 cases par 100, 000 persons per year. Prognostic indices of autoimmune hepatitis Prognostic indices before treatment Outcome AST≥ 10 -fold normal or 50% 3 -year mortality Prognostic indices after treatment HLA-B 8, DR 3 or Multilobular necrosis DR*0301 and failure to AST ≥ 5 fold normal + Bridging necrosis or 82% cirrhosis at 5 year 45% improve on gamma globulin ≥ 2 fold 90% 10 -year mortality multilobular necrosis 5 -year mortality treatment; normal hyperbilirubinemia after 2 weeks Failure to enter remission within 4 AST< 10 -fold normal + Cirrhosis 58% 5 -year mortality 49% cirrhosis at 15 years HLA-DR 4 or year and first sign of gamma globulin < 2 -fold 10% 10 -year mortality DRB 1*0401 decomposition normal AST, serum aspirate amino Interface hepatitis 17% cirrhosis at 5 years C 4 A gene deletion transfers level; HLA, human Normal 5 -year survival leukocyte Comments Associated with HLA-DR 3 Onset at young age Severe inflammation at High mortality rate presentation Relapse propensity Treatment failure common Liver transplantation frequent Onset in old age woman concurrent High mortality rate immunologic diseases to glucocorticoids Low serum complement level Early-onset disease

Clinical manifestations of Autoimmune hepatitis FINDINGS Symptoms Fatigue Upper abdominal discomfort Pruritus (mild) Anorexia Polymyalgias Diarrhea Cushingoid features Fever (≤ 40ºC) Physical findings Hepatomegaly Jaundice Splenomegaly Spider enigmas Ascites Encephalopathy Concurrent immune diseases

Clinical manifestations of Autoimmune hepatitis Laboratory features Aspirate aminotransferase level elevation Hyperbilirubinemia Alkaline phosphatase level ≥ 2 fold normal Immunoserologic markers SMA, ANA, or anti-LKM 1 Pronuclear antineutrophil cytoplasm Antiasialoglycoprotein receptor Antiactin Anti-liver cytosol 1 Anti-soluble liver antigen/liver-pancreas ANA, antinuclear antibody; anti-LKM 1, antibody to liver/ kidney type 1; SMA, smooth muscle antibody.

Treatment indications Indications Findings Absolute Relative None Clinical Incapacitating Mild or on symptoms Relentless clinical Laboratory AST ≥ 10 -fold normal AST 3 -to 9 -fold normal AST< 3 -fold normal AST≥ 5 -fold normal and gamma globulin ≥ 2 -fold normal AST<5 -fold normal and gamma globulin <2 -fold normal Severe cytopenia Histological Bridging necrosis Interface hepatitis Inactive cirrhosis Multilobular necrosis Portal hepatitis Decompensated cirrhosis with variceal bleeding AST, serum aspartate amino transfers level. Asymptomatic with mild laboratory changes Previous intolerance to prednisone and/or azathioprine

Treatment regimens Single drug therapy (mg/day) prednisone 1 week× 60 mg 1 week× 40 mg 2 weeks× 30 mg 20 mg unit end point OR COMBINATION THERAPY Prednisone (mg/day) + 1 week× 30 mg 1 week× 20 mg 2 weeks× 15 mg 10 mg until end point Azathioprine (mg/day) 50 mg until end point

Drug- related side effects 1. Prednisone Cosmetic changes, such as facial rounding, dorsal hump formation, obesity, acne, or hirsutism, occur in 80% of patients after 2 years of treatment regardless of regimen. Severe side effects, including osteopenia with vertebral compression, diabetes, cataracts, emotional lability, and hypertension, usually develop only after protracted therapy (more than 18 months) and on the higher dose prednisone schedule (20 mg/day).

Drug- related side effects 1. Prednisone Premature discontinuation of treatment is justified in 13% of patients, mainly because of intolerable obesity, cosmetic changes, or osteoporosis.

Drug- related side effects 2. Azathioprine Cholestatic hepatotoxicity, nausea, emesis, rash, and cytopenia. These side effects occur in fewer than 10% of patients treated with 50 mg/day and reverse with a reduction in dose or termination of therapy. Therefore, azthioprine with prednisone is preferred to prednisone alone because the combination produces fewer glucocorticoid related side effects during comparable periods of treatment (10% versus 44%).

B) Liver transplantation When decompensated patients with multilobular necrosis have at least at one laboratory parameter that fails to normalize or hyperbilitubinemia that does not improve during a 2 -week treatment period, the immediate mortality rate is high and evaluation for liver transplantation is warranted.

Treatment End Points Prednisone + azathioprine Or Prednisone alone (higher dose) Nosymptoms AST ≤ 2 x normal GG normal. Normal or minimalhistologic activity Sustained remission Relapse Worsening AST and/or bilirubin level ≥ 67% Worsening histologic activity Stable liver function Improvement in all aspects Failure to satisfy remission criteria Decompensation Protracted therapy (≥ 3 years) Repeat therapy Chronic therapy Liver transplantation 2 nd remission No therapy Sustained remission 2 nd relapse Indefinite low-dose Prednisone or azathioprine Indefinite low-dose Prednisone OR Indefinite azathioprine Intolerable symptoms Vertebral Compression Cytopenia

PRIMARY BILIARY CIRRHOSIS Epidemiology 1. Primary biliary cirrhosis (PBC) is found in all races. 2. Approximately 90 – 95% of patients are female. 3. Age of onset typically ranges from 30 to 70.

Immunologic abnormalities 1. Antimitochondrial antibody (AMA). § Detected in 95% of patients with PBC. 2. Increased levels of serum immunoglobulins. § Increased levels of a serum Ig. M that is immunoreactive and highly cryoprecipitable.

3. Association with other autoimmune diseases § Thyroiditis, hypothyroidism. § Rheumatoid arthritis. § CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectases). § Sjögren’s syndrome. § Scleroderma.

Pathogenesis Two related processes cause hepatic damage in PBC A-The first process Is chronic destruction of small bile ducts, presumably mediated by activated lymphocytes. cytotoxic T

B-The second process Is chemical damage to hepatocytes in areas of liver where bile drainage is impeded by the destruction of the small bile ducts. The destruction of bile ducts eventually leads to portal inflammation and scarring, and ultimately to cirrhosis and liver failure.

Hepatic histology Four histological stages of PBC have been identified. Stage I Damaged bile ducts are usually surrounded by a dense infiltrate of mononuclear cells, most of which are lymphocytes.

Stage I: Florid bile duct lesion. The epithelial cell lining of a small duct is infiltrated with lymphocytes

Stage II The lesion is more widespread. There may be reduced numbers of normal bile duct within portal triads and increased numbers of atypical, poorly formed bile ducts with irregularly shaped lumina. There is diffuse portal fibrosis and mononuclear cell infiltrates within triads. Inflammation may spill into the surrounding periportal areas.

Stage II : A typical bile duct hyperplasia is seen. There are tortuous bile ducts with inflammatory cell infiltrate consisting of primarily lymphocytes and few neutrophils.

Stage III Similar to stage II except that fibrous septa extend beyond triads and form portal-to-portal bridges.

Stage III : Portal-to-portal fibrous septum is shown (masson trichrome).

Stage IV Represents the end stage of the lesion, with frank cirrhosis and regenerative nodules. The findings may be indistinguishable from other types of cirrhosis. However, a paucity of normal bile duct in areas of scarring suggests the possibility of PBC.

Stage IV: There is a noncaseating granuloma in the center of and portal triads are linked by bands of connective tissue and inflammatory cells. (Masson trichrome).

Clinical features Symptoms About 48 – 60% of patients are asymptomatic at the time of diagnosis. The symptoms and signs of PBC are due to longstanding cholestasis.

1 - Fatigue Most common symptom. 2 - Pruritus The earliest specific complaint of PBC is pruritus. 3 - Malabsorption Impaired secretion of bile leads malabsorption of the fat-soluble vitamins A, D, E and K, and calcium.

4 - Osteoporosis Osteopenic bone disease occurs in at least 25% of PBC patients. The pathogenesis is still unclear. Osteomalacia is uncommon and occurs only in home -bound patients who have advanced PBC and little exposure to sunlight.

Physical examination 1. Hepatomegaly is found in approximately 43 -70% of patients. 2. Splenomegaly is present in 16 -35%. 3. Skin abnormalities: § Hyperpigmentation that resembles tanning is due to melanin, not bilirubin, in early-stage PBC. § Excoriations may be diffuse due to scratching caused by intractable pruritus. § Jaundice usually presents later in the course of the disease. § Xanthelasma and xanthomata correlate with hypercholesterolemia. q Less than 5% of patients will eventually develop xanthomata.

Xanthelasma Xanthomata are found on the palms of the hands and soles of the feet, over extensor surfaces of the elbows and knees, in tendons of the ankles and wrists, and on buttocks.

Bilateral plantar xanthomatas in the palms of a patient with PBC.

5 - Eyes: Kayser-Fleischer rings are rare and result from copper retention.

PRIMARY SCLEROSING CHOLANGITIS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibrosing inflammation of both the intrahepatic and extrahepatic biliary tree. The histopathologic evolution of (PSC) results in irreversible damage to the bile ducts and ultimately leads to cholestatic, cirrhosis, liver failure, and premature death from liver failure unless liver transplantation is pe 4 rformed.

Long-term follow up of patients with (PSC) has revealed a high frequency of colon and bile duct cancers, both of which are probably related to chronic inflammation of the colon and bile ducts. Although multiple medical and surgical therapies have been evaluated for the treatment of (PSC), there is currently no therapy that achieves complete clinical, biochemical and histologic remission. Liver transplantation continues to be an important therapeutic intervention for the management of patients with end-stage PSC.

Primary versus secondary sclerosing cholangitis Primary ▪With or without inflammatory bowel disease ▪Chronic cholestatis Presence of antineutrophil cytoplasmic antibodies (ANCA) Secondary ▪ Biliary surgery ▪ Choledocholithiasis ▪ Trauma ▪ Ischemia ▪ Chemical injury of the bile ducts (e. g. , ▪ chemotherapy, Infectious agents Clinical setting ▪ Congenital anomalies of the bile ducts ▪ Human immunodeficiency virus (HIV)infection ▪ Malignancy ▪ Idiopathic adulthood ductopenia ▪ Amyloidosis Ducts involved Intrahepatic and extrahepatic (classic or global) ▪ Hodgkin's disease Perihilar and extrahepatic

Clinical features and presentation 1) PSC is predominantly a disease of middle-age men; approximately 67% of patients are male, with a mean age of approximately 40 years at the time of diagnosis. 2) PSC usually presents insidiously and in a variety of ways: S Asymptomatic elevation of liver biochemical tests. S Pruritus, fatigue, jaundice. S Recurrent bacterial cholangitis. S Complications of cholestatsis. § Prevalence : 8. 5 cases per 100. 000 population. § Histologic findings.

The main features include Periductal fibrosis, inflammatory, and bile duct proliferation alternating with ductal obliteration and ductopenia.

Symptoms and signs of PSC at diagnosis Symptoms Fatigue Pruritus Jaundice Weight loss Fever Variceal bleed Ascites -------------------------- Signs Hepatomegaly Jaundice Splenomegaly Hyperpigmentation Xanthomas

Liver biochemical tests in PSC at diagnosis Test Patients with abnormal results (%) Serum alkaline phosphate 99 Serum aminotransferases 95 80 Antinuclear cytoplasmic antibody (ANCA) Serum bilirubin 65 Anti-smooth muscle antibody 55 Antinuclear antibody 35 Hypergammaglobulinema 30 Serum albumin 20 Prothrombin time 10

Hepatic histology in PSC Onion skin lesion of P SC Bile duct is obliterated and surrounded by fibrous tissue

The radiologic features most commonly seen in PSC include: Diffusely distributed multifocal annular strictures with intervening segments of normal or slightly ecstatic ducts. Short band-like strictures. Diverticulum-like outpouching.

ERCP showing stricture of the common hepatic duct PSC is associated with inflammatory bowel disease in over 75% of cases , most commonly chronic ulcerative colitis.

3) Complications specific to PSC S Bacterial cholangitis. S Biliary stone disease. S Dominant stricture. S Cholangiocarcinoma.

Treatment Management goals: Relieve symptoms. Prevent or treat complications. Halt progression of disease. Optimize timing of liver transplantation.

Managments of Complications specific to Primary sclerosing cholangitis 1) Bacterial cholangitis: Should be treated with broadspectrum i. v. antibiotic ciprofloxacin. 2) Stricture: should be treated endoscopically or radiologically with ballon dilation. 3) Cholangiocarcinoma: Carries a poor prognosis and responds poorly to chemotherapy or radiation therapy. Liver transplant is contraindicated.